HETEROCYCLES

■ Contents

■ Photochemical Synthesis of Benzopyrimidosemibullvalenes from Benzopyrimidobarrelenes

Kazue Ohkura,* Mikiko Kudo, Tetsuya Ishihara, Ken-ichi Nishijima, and Koh-ichi Seki

*Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Abstract

UV irradiation (λ= 254 nm) of 5-fluoro-1,3-dimethyluracil with naphthalene afforded a novel benzopyrimidosemibullvalene derivative with H and F atoms remaining intact on the newly constructed moiety. It was found that the semibullvalene could be derived from the initially produced barrelene derivative during irradiation.

■ A Ring-opening Cross-metathesis Reaction of N-Trialkylsilyl 2-Azabicyclo[2.2.1]hept-5-en-3-one with Allyltrimethylsilane

Minoru Ishikura,* Miyako Hasunuma, and Kazuo Yanada

*Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Abstract

Subjection of N-trialkylsilyl-2-azabicyclo[2.2.1]hept-5-en-3-one (1) to a ring-opening cross-metathesis reaction with allyltrimethylsilane in the presence of Grubbs’ catalyst was found to allow the predominate formation of pyrrolidine (3) over pyrrolidine (4).

■ Palladium-catalysed Synthesis of Pyrimidines

Truls Ingebrigtsen, Irene Helland, and Tore Lejon*

*Faculty of Science, Departmentof Chemistry, University of Tromsø, N-9037 Tromsø, Norway

Abstract

Satisfactory yields of 4-substituted pyrimidines and bicyclic pyrimidines are produced from α-methyl or α-methylene ketones when reacted with formamide and tetrakis(triphenylphosphine)palladium(0) or a 1:2 mixture of palladium(II) acetate and triphenylphosphine as catalysts. Under the same reaction conditions pyridines or imidazole are formed from 1,3- or 1,2-diketones.

■ Natural Bond Orbital Analysis of Pericyclic and Pseudopericyclic 1,5-Electrocyclizations of Conjugated Azides

Kazuaki Fukushima* and Hideo Iwahashi

*Wakayama Medical University, Wakayama Medical University

Abstract

We have carried out calculations of energetic, structural and electronic properties for 1,5-electrocyclizations of conjugated azides at the B3LYP/6-31+G(d) level of theory. Analyses of the second-order perturbative energy lowering for interaction between donor and acceptor natural bond orbitals at the RHF/6-31+G(d) level of theory have revealed conjugated group dependent pericyclic and pseudopericyclic nature of the reactions.

■ Synthesis and Structure of Dipyrido-1,4-dithiins

Beata Morak, Krystian Pluta,* Kinga Suwinska, Miroslawa Grymel, Céline Besnard, Marc Schiltz, Christian Kloc, and Theo Siegrist

*Department of Organic Chemistry, The Medical University of Silesia, Jagielloñska 4, 41-200 Sosnowiec, Poland

Abstract

Synthesis, properties and reactions of two isomeric dipyrido-1,4-dithiins of the C_2h and C_2v symmetry are described. Their structure determination and identification are based on spectroscopic methods (¹H and ¹³C NMR, HETCOR, gHMBC and MS), physical properties (mp and R_f), the 1,4-dithiin ring opening reactions and finally X-Ray analysis. A very unusual type of the Smiles rearrangement (S→S, the pyridyl group migrates from one sulfur atom to another) during the 1,4-dithiin ring opening with sodium methanethiolate enabling isomerization of dithiin with the C_2h symmetry to dithiin with the C_2v symmetry is found.

■ Stereocontrolled Synthesis of New Tetrahydrofuro[2,3-d]thiazole Derivatives via Activated Vinylogous Iminium Ions

Rade Markovic,* Marija Baranac, Peter Steel, Erich Kleinpeter, and Milovan Stojanovic

*Faculty of Chemistry, University of Belgrade, Studentski trg 16, P.O.Box 158, 11001 Belgrade, Serbia and Montenegro

Abstract

Heterocyclization of (Z)-5-(2-hydroxyethyl)-3-methyl-4-oxothiazo-lidines, bearing electron-withdrawing groups conjugated to an exocyclic double bond at C(2)-position, afforded under reductive conditions, cis-tetrahydro-furo[2,3-d]thiazole derivatives. The reactions of these functionalized push-pull β-enamines occur in a stereocontrolled fashion via activated vinylogous N-methyliminium ions, which are trapped by an internal hydroxyethyl group.

■ Synthesis of 4,6-Diaryl-4,6,7,8-tetrahydro[1,4]oxazepino[4,3-c]sydnone

Zhanbin Zhang* and Xinfang Duan

*Department of Chemistry, Beijing Normal University, Beijing, 100875, China

Abstract

Seven-membered ring fused sydnones, 4,6-diaryl-4,6,7,8-tetrahydro[1,4]oxazepino[4,3-c]sydnones (2) were prepared via oxa-Pictet-Spengler reaction of 3-(3-phenyl-3-hydroxypropyl)sydnone (1) with aromatic aldehydes in the presence of Lewis acid. The reactions gave two stereoisomers ( cis- and trans-), and the cis- isomers were the major products.

■ Asymmetric Synthesis of (2R,3R,4R)-3-Hydroxy-4-methylproline via Chromium(II) Chloride-mediated Coupling Reactions of (S)-Garner Aldehyde with Crotyl Bromide

Haruko Inaba, Yukiko Hiraiwa, Satoshi Yoshida, Mina Tamura, Asako Kuroda, Aki Ogawa, Yutaka Aoyagi, Akihiro Ohta, and Koichi Takeya*

*School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

Abstract

Efficient synthesis of (2R,4R,4R)-3-hydroxy-4-methylproline (1a), which is an antipode of the component of potent antifungal echinocandins, from (S)-Garner aldehyde (2a) has been established. The key step is chromium(II) chloride-mediated coupling reactions with crotyl bromide giving homoallyl alcohols (4a) and (4a’) in a ratio of 83:17.

■ New Synthesis of t-Butyl 1,2-Dihydro-1-oxaazulene-3-carboxylates Using Lithium Trimethylsilyldiazomethane

Susumu Tsuchida, Yoshiyuki Hari, and Toyohiko Aoyama*

*Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan

Abstract

Lithium trimethylsilyldiazomethane reacts with t-butyl aryloxypyruvates to give t-butyl 1,2-dihydro-1-oxaazulene-3-carboxylates via alkylidenecarbene intermediates.

■ Five New Sulfur-containing Polybrominated Bisindoles from the Red Alga Laurencia brongniartii

Natsuki K. Kubota, Hajime Iwamoto, Yoshimasa Fukazawa, and Yasuto Uchio*

*School of Allied Medical Sciences, Faculty of Medicine, Kagoshima University, Kagoshima 890-8544, Japan

Abstract

Five new sulfur-containing polybrominated bisindole (1˜5) were isolated from the red alga, Laurencia brongniartii, in addition to six related compounds (6˜11), which have been previously found in the Okinawan alga. The structures of these new bisindole metabolites were elucidated on the basis of spectroscopic studies, as well as X-Ray crystallographic analysis of 1.

■ The First and Reliable Synthesis of Thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones via Their [4,3-c] Compounds by Dimroth Rearrangement

Tomohisa Nagamatsu* and Shoeb Ahmed

*Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka 1-1-1, Okayama 700-8530, Japan

Abstract

This paper describes a reliable and general synthesis of thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (5a) and its 2-substituted derivatives (5b-i) as a novel ring system prepared by nimble isomerization of their [4,3-c] compounds (4a-i), which were produced by condensation of 4-hydrazinothieno[3,2-d]pyrimidin-2(1H)-one (12) with appropriate triethyl orthoesters or by oxidative cyclization of 4-(benzylidenehydrazino)thieno[3,2-d]pyrimidin-2(1H)- ones (13c-i). The [1,5-c] isomers (5a-c) were further prepared by condensation of 3-amino-4-imino-2-oxo-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidine (16) with appropriate triethyl orthoesters as a synthetic method for a reliable structure of the tricyclic ring systems.

■ Synthesis of 3-Methoxyellipticine and Ellipticine by Friedel-Crafts Reaction of Indole-2,3-dicarboxylic Anhydride and Selective Demethylation

Yasuyoshi Miki,* Yoshiyuki Aoki, Yasuhiko Tsuzaki, Misako Umemoto, and Hajime Hibino

*Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1, Kowakae, Higashi-Osaka 577-8502, Japan

Abstract

Reaction of 1-benzylindole-2,3-dicarboxylic anhydride with 2,4,6-trimethoxypyridine in the presence of a Lewis acid gave 1-benzyl-3-(2,4,6-trimethoxynicotinoyl)indole-2-carboxylic acid as the sole product in high yield, which could be changed to 1-benzyl-3-(2,4,6-trimethoxynicotinoyl)indole. 1 Benzyl-3 (2,4,6-trimethoxynicotinoyl)indole was converted to 3 methoxy¬ellipticine and ellipticine by selective demethylation and triflation of the methoxy group.

■ Isothiazolo[3,2-b]-1,3,4-oxadiazole-5,5-dioxide: Synthesis of a New Heteropentalene System

Stephan Schmidt, Arne Kolberg, Lothar Hennig, Jens Hunger, and Bärbel Schulze*

*Department of Organic Chemistry, Leipzig University, Johannisallee 29, Leipzig 04103, Germany

Abstract

Monocyclic, acceptor-substituted N-aroylisothiazolium-2-imines (5a-d), easily available by cyclocondensation of 2-methyl-3-thiocyanato-2-butenal with aryl hydrazides, are described and the structure of new five-membered azomethine imines (5) is determined by X-Ray structure of 5a. The oxidation of 2-imines (5) with hydrogen peroxide in acetic acid gives 3-hydroperoxysultims (rac-cis 6) , -sultams (7), and 3-oxosultams (10). The 3-hydroxysultams (8a-d) are obtained by reduction of hydroperoxides (7). Surprisingly, after the dehydration of 8a-h and its 1,5-electrocyclization, a new type of heteropentalenes, the isothiazolo[3,2-b]-1,3,4-oxadiazole-5,5-dioxides (11) is formed.

■ Synthesis of 1,2-Disubstituted Imidazoles via Cross-Coupling and Substitution Reactions

Ingo Langhammer and Thomas Erker*

*Department of Medicinal/Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Wien, Austria

Abstract

Lithiation of imidazole compound (1) in position 2 and subsequent quenching with electrophiles provided a route to 1,2-diaryl-, 1-aryl-2-cycloalkyl- and 1-aryl-2-heterocyclyl-substituted imidazoles.

■ A Facile Synthesis of 2-Aminothiazolo[5,4-b]pyridines and 2-Aminobenzoxazoles via Cyclization of Thioureas

Ju Hee Yoon, Hyunmin Song, Sang Wong Kim, Gyoonhee Han, and Hea-Young Park Choo*

*Ewha Womans University, School of Pharmacy, Seoul 120-750, Korea

Abstract

2-Aminothiazolo[5,4-b]pyridines and 2-aminobenzoxazoles have been synthesized from 2-hydroxy-3-thioureidopyridine and 2-hydroxy-3- thioureidobenzene respectively via acid catalyzed cyclization, which were prepared by the reaction of isothiocyanates with 2-hydroxy-3-aminopyridine or 2-aminophenol. The hydroxyl group of N-(2-hydroxy-5-phenyl)- N’-phenyl thiourea reacted as nucleophile to thioureido carbon to give 2-aminobenzoxazoles, whereas that of N-(2-hydroxypyridino)-N’-phenylthiourea was reacted as leaving group upon nuclephillic sulfur of thiourea group in the presence of trifluoroacetic acid or phosphoric acid.

■ Synthesis of Substituted 1,3-Dimethyl-1H-quinoxalin-2-ones from Aniline Derivatives

Xun Li, Donghua Wang, Jifeng Wu, and Wenfang Xu*

*College of Pharmacy, Shangdong University, Jinan 250012, China

Abstract

Substituted 1,3-dimethyl-1H-quinoxalin-2-ones (7) have been synthesized through the procedures of acylation, nitration, reduction, intramolecular alkylation, oxidation, and N-methylation starting from 3,4-disubstituted aniline.

■ Comparative Structural Studies of 4-Diazopyrazole Derivatives by X-Ray Diffraction and Theoretical Investigation

Giuseppe Daidone,* Benedetta Maggio, Maria Valeria Raimondi, Gabriella Bombieri, Nicoletta Marchini, and Roberto Artali

*Department of Pharmaceutical Chemistry and Technology, University of Palermo, Via Archirafi 32, 90123 Palermo,

Abstract

The X-Ray crystal and molecular structures of the 4-pyrazol derivatives 3-methyl-4-diazo-5-benzamido-1H-pyrazole (4) and 3-benzamido-5-methyl-1H-pyrazole (3) have been determined. A dimeric structure has been found for the first and polymeric for the second. A comparison of 4 with 1,3-dimethyl-4-diazo-5-benzamido-1H-pyrazole (2) shows differences in the geometrical parameters of the pyrazole ring due to electron delocalization in 2 consequent to the nitrogen negative charge in the latter. Theoretical investigation at the density functional theory (DFT) level shows difference in the molecular electronic distribution of 2 and 4, in agreement with the structural parameters and the IR stretching frequencies of the respective carbonyl moieties.

■ A Practical Synthesis of 1-Alkyl-3-amino-4-aryl-1,8-naphthyridin-2-(1H)-one, a Partial Structure of ACAT Inhibitor SMP-797

Hitoshi Ban,* Masami Muraoka, Kouji Morisita, and Naohito Ohashi

*Research Division, Sumitomo Pharmaceuticals Co., Ltd., 1-98, Kasugadenaka 3-chome, Konohana-ku, Osaka 554-0022, Japan

Abstract

3-Amino-4-[3-(3-benzyloxypropoxy)phenyl]-1-butyl-1,8- naphthyridin-2(1H)-one, which is a naphthyridine part of a potent ACAT (acyl-CoA: cholesterol acyltransferase) inhibitor SMP-797, was effectively synthesized from m-bromophenol in 5 steps without isolating intermediates. The synthesis involved the intramolecular aldol reaction as a key step.

■ New Vermistatin Derivatives Isolated from Penicillium simplicissimum

Shin-ichirou Komai, Tomoo Hosoe, Takeshi Itabashi, Koohei Nozawa, Takashi Yaguchi, Kazutaka Fukushima, and Ken-ichi Kawai*

*Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

Four new vermistatin derivatives, dihydrovermistatin (1), acetoxy- dihydrovermistatin (2), hydroxydihydrovermistatin (3), and penisimplicissin (4) were isolated along with vermistatin (5), penicillide, and funicone from the extract of Penicillium simplicissimum IFM 53375. The structures of 1 - 4 were determined by spectroscopic and chemical methods.

■ Friedländer Reactions of Triacetylmethane - Unusual Distribution of Products -

A. F. M. Motiur Rahman, Youngjoo Kwon, and Yurngdong Jahng*

*College of Pharmacy, Yeungnam University, Kyongsan 712-749, Korea

Abstract

Friedländer reactions of triacetylmethane with selected β-amino-α,β- unsaturated aldehydes afforded pyridoheterocycles and their 2-methyl derivatives instead of triheteroarylmethane.

■ Synthesis of Benzobicyclo[2.2.1]heptylimidazoles as Conformationally Constrained Adrenergic Receptor Antagonists

Jari Yli-Kauhaluoma,* Aki Laine, Jari Ratilainen, and Arto Karjalainen

*Technical Research Centre of Finland, VTT Processes, P.O. Box 1602, FI-02044 VTT, Finland

Abstract

A facile method for the preparation of conformationally rigid analogues of the adrenergic α-2 receptor antagonist atipamezole and the adrenergic α-2 receptor agonist medetomidine has been developed. The efficient benzyne [4+2] cycloaddition reaction was used to give the core 7-acetylbenzonorbornadiene structure, which was subsequently elaborated to the corresponding imidazole-based syn and anti isomers by means of the classical Bredereck’s method.

■ Synthesis of Novel Triphenylene-Type Cations Containing Both Thiophene Rings and a Tropylium Ion Ring. Cyclohepta[e]thieno[2,3-g]benzodithiophenylium Ion and Cyclohepta[e]thieno[3,2-g]benzodithiophenylium Ion

Teppei Oyanagi, Yasuhiro Sakurai, and Kimiaki Yamamura*

*Department of Chemistry, Faculty of Science, Kobe University, Nada, Kobe 657-8501, Japan

Abstract

An isomeric pair of cyclohepta[e]thieno[g]benzodithiophenylium ions has been synthesized by an intramolecular Friedel-Crafts type reaction of 2(3)-thienyl-3(2)-cycloheptatrienylthiophenes in a one-pot reaction. These are the isoelectronic cations of triphenylene having both electron-rich and electron-deficient aromatic rings, thiophene and tropylium ion, respectively, in place of phenyl rings.

■ New Approach to the Synthesis of Non-benzenoid Aromatic Compounds, Functionalized 1-Azaazulene Derivatives: Cyclization Reactions of 2-Substituted Tropones with N-Silylenamine and Enamine

Norio Sakai, Naoto Hattori, Nanako Tomizawa, Noritaka Abe, and Takeo Konakahara*

*Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan

Abstract

The reaction of enamines with 2-subsituted tropones produced functionalized 1-azaazulene derivatives. When the reaction is conducted in an aprotic solvent, such as DMSO, the desired 1-azaazulene was obtained in 51% yield. The introduction of an electron-donating group on the enamine increased its nucleophilicity and improved the product yield. On the other hand, the reaction of enamines with 4-isopropyltropone-2-tosylate afforded a different 1-azaazulene derivative.